Effective anti-HIV vaccines remain elusive while HIV infection rates are increasing. A key attribute of a successful anti-HIV vaccine formulation should be the ability to provide active, protective anti-HIV antibodies (including mucosal) and CMI responses. Human enteroviruses are excellent vaccines: like the closely related polioviruses, infection by any of the six group B coxsackieviruses (CVB1-6) generate life-long T (helper and cytotoxic) and B (including mucosal) cell anti-CVB type specific immunities in humans. We hypothesize that chimeric CVB can both express antigenic HIV-1 polypeptides and elicit protective anti-HIV-1 humoral and cellular immune responses in experimentally inoculated mice. The testing of this hypothesis is the objective of this proof-of-concept R21 grant proposal. Two specific aims of the proposal are proposed to meet this objective, experiments for which will be carried out concurrently. We will: [1] Determine the extent to which HIV-1 gp120 V3 loop region antigens are presented to the immune system during replication of the chimeric CVB3 strain in mice. CVB3 strains that express V3 loop containing gp120 polypeptides will be characterized in cell cultures and mice for replication and immunogenicity. [2] Investigate whether the murine host immune response against the gp120 antigen is augmented through the co-expression of murine IL-2 (mIL-2) linked to the gp120 polypeptide. Murine IL-2 will be expressed with a gp120 polypeptide as a fusion protein to determine the extent to which mIL-2 affects the murine immune responses to the antigen in comparison to a control CVB3 vector expressing just the gp120 fragment. Our long-term goal is the development of a chimeric CVB-based vaccine vector system for prophylactic, and possibly therapeutic, uses against HIV infection. Results from this proof-of-principle proposal will test feasibility within an HIV framework.